Alzheimer's disease (AD) afflicts more than 5.8 million people in the US at an estimated cost greater than $200 billion per year. Currently approved drugs offer only short-term symptomatic relief but do not alter disease progression. The neuritic plaques that are a hallmark of AD brain result from increased generation and/or decreased clearance of the amyloid beta peptide (A?) which originates from amyloid precursor protein (APP). Processing of APP occurs by two pathways ? sequential ?-secretase and ?-secretase cleavages to generate soluble amyloid precursor protein beta (sAPP?) and A? or cleavage by ?-secretase to generate soluble amyloid precursor protein alpha (sAPP?), a pro-cognitive peptide that may prevent disease progression in AD. Sorting protein-related receptor with A-type repeats (SORLA) plays a key role in modulating the intracellular trafficking of APP through the secretory and endocytic pathways that regulates its commitment towards the amyloidogenic or non-amyloidogenic processing and constitutes a promising target which could be modulated by innovative therapeutic strategies to enhance sAPP?. SORLA is significantly reduced in brain tissue from late-onset AD (LOAD) patients (Scherzer et al. 2004), numerous studies have linked impaired SORLA with an increased risk of sporadic AD (Campion et al. 2019). Importantly, SORLA overexpression has been shown to increase sAPP? and reduce A? in models of AD. Mechanisms by which SORLA regulates APP processing include interaction with APP in the trans-Golgi thereby limiting the pool of endosomal APP available for amyloidogenic proteolysis; inhibition of the dimerization of APP, thus reducing ?-secretase cleavage; and its binding A? through the VPS10P domain, targeting it to lysosomes for degradation. Here, we propose utilizing our high-throughput screening (HTS) assay, iterative screening flowscheme, and the large UCLA compound library to identify compounds that enhance SORLA protein levels in neurons. In the primary HTS screen, ?hits? that increase SORLA will be identified. In the secondary screen validated hits would be evaluated in neuronal cells. Prioritized hits will be evaluated for effects on SORLA in patient iPSC's and ex vivo in organotypic slice cultures. Brain penetrance on promising hits planned to be done by in vivo pharmacokinetic (PK) analysis. Finally, we will determine the mechanisms/target by which hits induce SORLA enhancement using the CEREP Bioprint profile panel, affinity purification/proteomics and in silico target identification using the similarity ensemble approach. In Aim1, we plan to conduct high throughput screening (HTS) in CHO-7W cells to identify `hits' that enhance SORLA levels and validate them in SH-SY5Y cells. In Aim2, we will conduct testing of validated hits for ability to enhance SORLA and sAPPalpha levels in primary neuronal cultures and in AD patient derived iPSC. In Aim3, we will evaluate prioritized hits in organotypic slice cultures from hippocampal tissue of an AD mouse model and assessment of brain permeability. In Aim4, we will conduct target identification analysis using the best hits along with analysis of potential transcription factor binding sites.